ES2355421T3 - PREVENTIVE OR THERAPEUTIC AGENT FOR DISEASES ASSOCIATED WITH HERPES VIRUS. - Google Patents

Abstract

A herpes anti-virus agent characterized by the combination of a compound of general formula (I): in which Z is a 1,2,4-oxadiazol-3-yl or 4-oxazolyl group; A is a phenyl group that is substituted with at least one methyl group and which may also have 1 or 2 substituents selected from the group consisting of a methyl group or ** Formula ** halogen atoms, or a 5-indanyl group; with a polymerase inhibitor selected from acyclovir, valacyclovir and famciclovir; wherein the compound of general formula (I) and the polymerase inhibitor must be administered separately.

Description

Technical Field This invention relates to a medicament, in particular a medicament useful for preventing and treating diseases associated with the herpes virus. Background 5 Viruses belonging to the Herpesviridae family cause various infectious diseases in humans and animals. For example, it is known that varicella zoster virus (VZV) causes chickenpox and shingles, and herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) cause infections such as cold sores, genital herpes, etc., respectively. Additionally, in recent years infectious diseases caused by herpes viruses such as cytomegalovirus (CMV), EB virus (Epstein-Barr virus; EBV), the 10 human herpes viruses 6, 7 and 8, etc. have been elucidated. Currently, drugs based on nucleic acids, called "polymerase inhibitors", such as acyclovir (ACV) and its prodrugs, that is, valacyclovir (VCV), famciclovir (FCV), etc., are used as agents against herpes viruses such as VVZ and VHS. These nucleic acid series medications are monophosphorylated to form nucleoside monophosphates by viral thymidine kinase encoded by VZV or HSV and are subsequently converted into triphosphate compounds by cellular enzymes. Finally, triphosphorylated nucleoside analogs are incorporated during replication of viral genomes by the DNA polymerase of herpes viruses to suppress the extension reaction of viral DNA chains. Since the reaction mechanism of existing herpes anti-virus agents is based on the effect of "competitive inhibition" for deoxynucleoside triphosphates, as described above, it is necessary to use these drugs at a high concentration to exert their antiviral effects In reality, these herpes anti-virus drugs of the nucleic acid series are administered clinically at a dose as high as several hundred mg to several grams per day. Because these nucleic acid series drugs can be incorporated into the genomic DNA of the host through the host DNA polymerase, their mutagenicity is also of concern. 25

 On the other hand, several drugs not based on nucleic acids and with anti-herpes virus activity have been described lately. For example, an amide or sulfonamide derivative has been described which suppresses the HSV helicase-primase enzyme complex and shows anti-HSV-1 activity and anti-CMV activity, as represented by the following Formula (G), in which the N atom is substituted with a thiazolylphenylcarbamoylmethyl group or the like (for example, see Patent Reference 1). 30 (In the formula, R is hydrogen, a lower alkyl, amino, a lower alkylamino or the like; R2 is hydrogen or a lower alkyl; Q may be absent or, when it exists, Q represents a methylene; R3 is hydrogen, an alkyl lower or similar; R4 is an unsubstituted or substituted (lower) phenyl alkyl, 1-indanyl, 2-indanyl, (lower cycloalkyl) - (lower alkyl), (Het) - (lower alkyl) or the like; R5 is a phenyl sulfonyl, 1- or 2-naphthylsulfonyl, (Het) -sulfonyl, (substituted or unsubstituted phenyl) -Y- (CH2) nC (O), (Het) - (CH2) nC (O) or similar, where Y is O or S and n is 0, 1 or 2; for details see Patent Reference 1).

image 1

 In addition, an amide or sulfonamide derivative having anti-HSV-1 activity and anti-CMV activity is described as represented by the following Formula (H), in which the nitrogen atom is substituted with a thiazolylphenylcarbamoylmethyl group (e.g., See Patent Reference 2.) (In the formula, R1 is NH2; R2 is H; R3 is H; R4 is CH2Ph, CH2- (4-pyridyl), CH2-cyclohexyl or the like; and R5 is CO-40 ( substituted phenyl), CO- (substituted or unsubstituted hetero ring) or the like; see Publication for more details.)

image 1

 The present inventors previously found an amide compound substituted with a thiazolylphenylcarbamoylmethyl group and with a favorable anti-herpes virus activity, such as that represented by the following formula in which the amide group nitrogen atom is directly substituted with an aromatic aryl group or with a heteroaryl group as ring A, or the salt thereof. Thus, the inventors filed a patent application (Patent Reference 3 and Patent Reference 4). 5

image 1

(In the formula, R1 and R2 represent -H, -alkyl, -NRaRb or the like; A represents -aryl which may have a substituent (s), -heteroaryl which may have a substituent (s) or similar; X represents CO or SO2; R3 represents -aryl which may have one (s) substituent (s), -heterocycle which may have a substituent (s) or the like; for more details see Publication.)

 In addition, a compound represented by the following formula is described in an application of the present applicant (Patent Reference 5) which was published after the priority date of the present application. The compound is optionally used in combination with acyclovir, valacyclovir or famciclovir.

image 1

(In the formula, Z represents 1,2,4-oxadiazol-3-yl, 4-oxazolyl or the like; A represents an aryl group or the like that can have substituent (s); X represents CO or SO2 and R3 represents a heterocycle or similar that a substituent (s) may have. For more details see the Publication.) 15

 On the other hand, with regard to compounds that have helicase-primase inhibitory activity but that have a skeleton represented by the following formula that is different from the present application, there are reports on the effect of their simultaneous use with acyclovir (for example, see Patent Reference 6).

image 1

(See Publication for formula symbols.) 20

 Patent Reference 1: International Publication No. 97/24343.

 Patent Reference 2: International Publication No. 00/29399.

 Patent Reference 3: International Publication No. 02/38554.

 Patent Reference 4: International Publication No. 03/95435.

 Patent Reference 5: International Publication No. 05/014559. 25

 Patent Reference 6: Specification of German Patent Application Publication No. 10129717.

Description of the Invention

Problems that the invention has to solve

 To this day, there is a great demand for the development of an anti-herpes 30 virus agent that has high safety.

Means to Solve Problems The present inventors have carried out extensive studies on agents to prevent and treat diseases associated with herpes viruses and, as a result, found two or more compounds that had anti-herpes virus activity based on helicase inhibitory activity. cousin In addition, the helicase-primase inhibitor was used separately with a polymerase inhibitor generally used as an anti-herpes virus agent. 5 That is, the present invention relates to

 (1) a herpes anti-virus agent characterized by the combination of a helicase-primase inhibitor, a compound N- {2 - [(4-phenyl substituted) amino] -2-oxoethyl} tetrahydro-2H-thiopiran- 4-carboxamide represented by the following general formula (I), with a polymerase inhibitor

 (The symbols of the formula have the following meanings, Z: a 1,2,4-oxadiazol-3-yl or 4-oxazolyl group, 10 A: a phenyl group that is substituted with at least one methyl group and may also have 1 or 2 substituents selected from the group consisting of a methyl group and halogen atoms, or a 5-indanyl group; the same will apply hereafter), and

image 1

 (2) the herpes anti-virus agent described in item (1) above, in which the polymerase inhibitor is selected from acyclovir, valacyclovir and famciclovir; wherein the compound of general formula (I) 15 and the polymerase inhibitor are to be administered separately.

 Preferably, the polymerase inhibitor is valacyclovir.

 In addition, it also refers to

 (3) a medicament for treating herpes virus infection, comprising (a) a pharmaceutical preparation containing as active ingredient the compound of general formula (I) and (b) a leaflet 20 indicating that said pharmaceutical preparation is used separately with an anti-herpes virus agent that contains as an active ingredient a polymerase inhibitor, where the polymerase inhibitor is selected from acyclovir, valacyclovir and famciclovir. Preferably, the polymerase inhibitor is valacyclovir.

 In addition, the invention also includes the following embodiments. 25

 (4) A composition for the treatment of herpes virus infection containing a compound of general formula (I) and a polymerase inhibitor, wherein the polymerase inhibitor is selected from acyclovir, valacyclovir and famciclovir; wherein the compound of general formula (I) and the polymerase inhibitor are to be administered separately.

 Preferably, the polymerase inhibitor is valacyclovir. 30

 (5) Use of the compound of general formula (I) for the manufacture of a medicament for use in the treatment of herpes virus infection by using it separately with a polymerase inhibitor, where the polymerase inhibitor is selected from acyclovir , valacyclovir and famciclovir.

 Preferably, the polymerase inhibitor is valacyclovir.

 (6) An agent for increasing the activity of a polymerase inhibitor in the treatment of infection with herpes viruses, which comprises the compound of general formula (I) as an active ingredient, where the polymerase inhibitor is selected from acyclovir, valacyclovir and famciclovir; wherein the compound of general formula (I) and the polymerase inhibitor are to be administered separately.

 Preferably, the polymerase inhibitor is valacyclovir.

 (7) An agent for the treatment of a herpes virus infection of a patient subject to treatment of herpes virus infection with a polymerase inhibitor, comprising as active ingredient the

compound of general formula (I), where the polymerase inhibitor is selected from acyclovir, valacyclovir and famciclovir; wherein the compound of general formula (I) and the polymerase inhibitor are to be administered separately. Preferably, the polymerase inhibitor is valacyclovir. (8) An agent for the treatment of herpes virus infection, in which the anti-herpes virus activity is increased compared to the administration of a polymerase inhibitor alone, comprising a combination of the polymerase inhibitor and the compound of general formula (I), where the polymerase inhibitor is selected from acyclovir, valacyclovir and famciclovir; wherein the compound of general formula (I) and the polymerase inhibitor are to be administered separately. Preferably, the polymerase inhibitor is valacyclovir. 10 (9) An agent for increasing anti-herpes virus activity in a patient to whom a polymerase inhibitor has been administered, comprising an effective amount of the compound of general formula (I), in which the polymerase inhibitor is selected between acyclovir, valacyclovir and famciclovir; wherein the compound of general formula (I) and the polymerase inhibitor are to be administered separately. Preferably, the polymerase inhibitor is valacyclovir. Effect of the Invention By separate administration of an acyclovir, valacyclovir or famciclovir polymerase inhibitor as a conventional anti-herpes virus agent, with a helicase-primase inhibitor of general formula (I) having a different mechanism of action, the agent Herpes anti-virus of the present invention achieved an anti-herpes virus activity. Therefore, it is particularly effective in cases where a sufficient therapeutic effect cannot be achieved only with a polymerase inhibitor. In addition, since the doses of both agents can be kept low by their separate use, it is possible to obtain a therapeutic effect that is similar or greater than that achieved in the case of a single respective administration, together with the decrease in the undesirable actions of both agents. involved Accordingly, the herpes anti-virus agent of the present invention is useful as an anti-herpes virus agent that is particularly safe for the prevention or treatment of different herpes virus infections such as chicken pox ("chikenpox") associated with VZV infection, shingles associated with recurrent latent VZV infection, cold sores and herpetic encephalitis associated with HSV-1 infection, genital herpes associated with HSV-2 infection. Best Mode for Carrying Out the Invention The helicase-primase inhibitor according to the present invention is a compound N- {2-30 [(4-phenylsubstituted) amino] -2-oxoethyl} tetrahydro-2H-thiopiran-4- carboxamide represented by the following general formula (I). In this description, it can sometimes be referred to simply as a "helicase-primase inhibitor" hereafter.

(The symbols of the formula have the following meanings. Z: a 1,2,4-oxadiazol-3-yl or 4-oxazolyl group, A: a phenyl group that is substituted with at least one methyl group and which may also have 1 or 2 substituents selected from the group consisting of a methyl group or halogen atoms, or a 5-indanyl group.)

image 1

 In addition, the polymerase inhibitor is a compound that inhibits the enzymatic activity possessed by a herpes virus DNA polymerase complex and its illustrative examples include nucleic acid-based drugs such as acyclovir (ACV) and its prodrugs valacyclovir (VCV), famciclovir (FCV).

 Particularly preferred is the VCV. 40

 The "anti-herpes virus agent characterized by the combination of a helicase-primase inhibitor with a polymerase inhibitor" of the present invention includes a pharmaceutical preparation for preventing or treating a disease associated with the herpes virus, which comprises a effective amount of a helicase-primase inhibitor of general formula (I) and an effective amount of a polymerase inhibitor such as acyclovir, valacichlor or famciclovir (separate administration) and a kit containing two pharmaceutical preparations; a herpes anti-virus agent as the first pharmaceutical preparation containing a helicase-primase inhibitor of the formula

General (I) as its active ingredient and another anti-herpes virus agent as a second pharmaceutical preparation containing an acyclovir, valacyclovir or famciclovir polymerase inhibitor as its active ingredient. In this regard, the two pharmaceutical preparations are administered separately through the same or a different route of administration.

 The "kit containing two pharmaceutical preparations" mentioned above contains two pharmaceutical preparations, each of which contains the respective active ingredients for separate use therapy of these active ingredients, and its example includes a package that may contain a supplementary pharmaceutical preparation. , such as a placebo, that facilitates administration in response to its period of administration following occasional demands or a viewing member. The term "separately" means that the first pharmaceutical preparation and the second pharmaceutical preparation are administered separately by the same or different route of administration, with the same or different frequency or range of administration. They are administered separately under suitable conditions of administration for the respective pharmaceutical preparations as regards the formulation of the pharmaceutical preparations, the route of administration, the frequency of administration, taking into account the bioavailability and stability of each pharmaceutical preparation. fifteen

 In addition, the "medicine for the anti-herpes virus treatment, comprising (a) a pharmaceutical preparation containing as an active ingredient a helicase-primase inhibitor of general formula (I) and (b) a leaflet indicating that said pharmaceutical preparation it is used separately with an anti-herpes virus treatment agent comprising a polymerase inhibitor (acyclovir, valacyclovir or famciclovir) as an active ingredient ”, means a medicine packaged for the anti-herpes virus treatment that comprises an effective amount of the preparation Pharmaceutical containing the helicase-primase inhibitor of general formula (I) as active ingredient, shown by (a), and the leaflet relating to the pharmaceutical preparation (a) mentioned above indicating that said pharmaceutical preparation is used separately with an agent of anti-herpes virus treatment that contains as an active ingredient a polymerase inhibitor (acyclovir, valacicl ovir or famciclovir) shown by (b). 25

 Next, the helicase-primase inhibitor of the medicine of the present invention, the compound N- {2 - [(4-phenylsubstituted) amino] -2-oxoethyl} tetrahydro-2H-thiopyran-4-carboxamide represented by the general formula (I).

 In the invention, the atoms of F, Cl, Br and I can be exemplified as a "halogen atom". 30

 The compound N- {2 - [(4-phenylsubstituted) amino] -2-oxoethyl} tetrahydro-2H-thiopiran-4-carboxamide represented by the general formula (I) may also be its hydrates, various species of solvates and polymorphic substances .

 In particular, the following compounds are desirable as compounds represented by the general formula (I). 35

 (1) A compound in which Z is a 1,2,4-oxadiazol-3-yl group.

 (2) A compound in which Z is a 4-oxazolyl group.

 (3) A compound in which A is a phenyl group that is substituted with at least one methyl group and may also have 1 or 2 substituents selected from the group consisting of a methyl group and halogen atoms. 40

 (4) A compound in which A is a 5-indanyl group.

 (5) A compound selected from the group consisting of

 N- (2,6-dimethylphenyl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopiran dioxide -4-carboxamide,

 N- (4-methylphenyl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopiran-4 dioxide -45 carboxamide,

 N- (4-methylphenyl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopiran-4 dioxide -carboxamide,

 N- (2-methylphenyl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopyran-4 dioxide -carboxamide, 50

 N- (2,4-dimethylphenyl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopyran dioxide -4-carboxamide,

 N- (3,4-dimethylphenyl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopiran dioxide -4-carboxamide,

 1,1- N-(2,3-dihydro-1H-inden-5-yl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2 -oxoethyl) tetrahydro-2H-thiopiran-4-carboxamide,

 1,1- N- (4-chloro-3-methylphenyl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H dioxide -5 thiopiran-4-carboxamide,

 1,1- N- (3-fluoro-4-methylphenyl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H dioxide -thiopiran-4-carboxamide,

 1,1- N-(3-fluoro-2,4-dimethylphenyl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro dioxide -2H-thiopiran-4-carboxamide, 10

 N- (3,5-Difluoro-4-methylphenyl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydroxide dioxide -2H-thiopiran-4-carboxamide,

 1,1- N- (2-fluoro-4-methylphenyl) -N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H dioxide -thiopiran-4-carboxamide,

 N- (2,3-dimethylphenyl) -N- (2 - {[4- (1,2,4-oxadiazol-3-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H dioxide -15 thiopiran-4-carboxamide,

 N- (2,4-dimethylphenyl) -N- (2 - {[4- (1,2,4-oxadiazol-3-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H dioxide -thiopiran-4-carboxamide,

 N- (2,6-dimethylphenyl) -N- (2 - {[4- (1,2,4-oxadiazol-3-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H dioxide -thiopiran-4-carboxamide, 20

 1,1- N- (4-fluoro-2,6-dimethylphenyl) -N- (2 - {[4- (1,2,4-oxadiazol-3-yl) phenyl] amino} -2-oxoethyl dioxide ) tetrahydro-2H-thiopiran-4-carboxamide,

 1,1- N- (2,3-dihydro-1H-inden-5-yl) -N- (2 - {[4- (1,2,4-oxadiazol-3-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopiran-4-carboxamide,

 1,1- N- (3-fluoro-4-methylphenyl) -N- (2 - {[4- (1,2,4-oxadiazol-3-yl) phenyl] amino} -2-oxoethyl) tetrahydro dioxide -25 2H-thiopiran-4-carboxamide,

 N- (4-Chloro-3-methylphenyl) -N- (2 - {[4- (1,2,4-oxadiazol-3-yl) phenyl] amino} -2-oxoethyl) tetrahydroxide dioxide -2H-thiopiran-4-carboxamide, and

 1,1- N- (3-fluoro-2,4-dimethylphenyl) -N- (2 - {[4- (1,2,4-oxadiazol-3-yl) phenyl] amino} -2-oxoethyl dioxide ) tetrahydro-2H-thiopiran-4-carboxamide. 30

 The herpes anti-virus agent of the present invention, characterized by the combination of a helicase-primase inhibitor of general formula (I) with a polymerase inhibitor (acyclovir, valacyclovir or famciclovir), can be prepared as separate pharmaceutical preparations for a kit, from one or two or more species of effective amounts of a helicase-primase inhibitor of general formula (I) and one or two species of effective amounts of an acyclovir, valacyclovir or famciclovir polymerase inhibitor, by means of a 35 method generally used using vehicles, excipients for drugs generally used in this field. The administration thereof can be oral by tablets, pills, capsules, granules, powders, liquids, or it can be by parenteral dosing by injections such as intravenous injections, intramuscular injections, external agents such as ointments, poultices, creams, jellies, poultices, aerosols, lotions, eye drops, eye ointments, suppositories, inhalation agents. 40

 As a solid composition for oral administration tablets, powders, granules are used. In such a solid composition, one or more active substances are mixed with at least one inert excipient, for example lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate. According to general methods, the composition may contain inert additives such as lubricants, for example magnesium stearate, disintegrants, for example sodium carboxymethyl starch, and auxiliary agents for dissolution. The tablets or pills may be coated with a sugar coating or with a soluble stomach or enteric coating.

 Examples of the liquid composition for oral administration include pharmaceutically acceptable emulsions, liquids, suspensions, syrups and elixirs in which inert solvents for general use such as purified water, ethanol can be incorporated. In addition to the inert solvents, the composition may also contain auxiliary agents such as solubilizing agents, wetting agents and suspending agents; sweetening agents; flavoring agents, aromatic agents and preservatives.

 Examples of injections for parenteral administration include aqueous or non-aqueous liquids, suspensions and sterile emulsions. Aqueous solvents include, for example, distilled water for injection and physiological saline. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (name of the pharmacopoeia). Such compositions may further contain isotonic agents, antiseptics, wetting agents, emulsifying agents, dispersing agents, stabilizing agents and auxiliary agents for dissolution. These are sterilized by filtration through bacteria-retaining filters, by incorporating sterilizing agents or by irradiation. Alternatively, they can be produced as a sterile solid composition and subsequently dissolved or suspended in sterile water or sterile solvents for injection before use. 10

 Examples of external agents include ointments, plasters, creams, jellies, poultices, aerosols, lotions, eye drops, eye ointments. The external agent contains bases for ointments, bases for lotions, aqueous or non-aqueous liquids, suspensions, emulsions used in a general manner. As bases for ointments or lotions, there may be mentioned as examples polyethylene glycol, propylene glycol, white petrolatum, white beeswax, castor oil hardened with polyoxyethylene, glycerol monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, polymer of carboxyvinyl.

 When a compound conventionally known through the aforementioned reference is used as a helicase-primase inhibitor of the present invention, the appropriate dose and the appropriate form of administration described in said reference can be employed. Preferably, a lower dose than the dose described in the reference is used, because a sufficient combined effect with a smaller amount can be obtained. In general, the appropriate daily dose of the new Compound (I) of the present invention, which is the active ingredient of the present invention, is 0.001 to 50 mg / kg / body weight, preferably 0.01 to 30 mg / kg / body weight, more preferably 0.05 to 10 mg / kg / body weight, for oral administration. For intravenous administration, the daily dose is 0.0001 to 10 mg / kg / body weight, preferably 0.001 to 1.0 mg / kg / body weight. The dose is administered once a day or in separate portions each day, and 25 is determined appropriately depending on each case, in terms of symptoms, age, sex. When Compound (I) is to be used as an external agent, it is desirable that the agent contain the compound of the present invention in an amount of 0.0001 to 20%, preferably 0.01 to 10%. The external agent is administered locally once a day or in several separate portions per day, depending on the symptom.

 On the other hand, the dose of the polymerase inhibitor of the present invention is decided in response to the activity of the polymerase inhibitor to be used. In the case of a polymerase inhibitor whose clinically appropriate dose and frequency of administration are already known, it is desirable to administer it at said clinical dose and with said frequency of administration. Alternatively, considering its synergistic effect with the helicase-primase inhibitor, it can be administered in an amount less than that. For example, in the case of ACV, VCV or FCV, your daily dose is generally 1 to 300 mg / kg, preferably 35 to 200 mg / kg, more preferably 10 to 150 mg / kg body weight in the case of oral administration, and its daily dose in the case of intravenous administration is 0.01 to 10 mg / kg, preferably 0.1 to 1.0 mg / kg body weight, respectively, and is administered once a day. day or dividing it into two or more times. The dose is optionally decided considering the symptoms, age and sex in response to individual cases. In addition, when used as an external preparation, an external preparation containing 0.0001 to 20%, preferably 0.01 to 10% of Compound (I) is desirable. It is administered topically one to several times a day in response to symptoms.

 The pharmaceutical composition of the present invention, which contains the helicase-primase inhibitor of general formula (I) and the acyclovir, valacyclovir or famciclovir polymerase inhibitor, is produced by preparing it in such a way that both components are contained in the respective amounts. corresponding to the aforementioned doses.

 The helicase-primase inhibitor of the present invention can be prepared by the method described in the aforementioned reference, and a commercially available product can be used as the polymerase inhibitor.

 Hereinafter, the typical production methods of Compound (I) as the helicase-primase inhibitor of the medicament of the present invention are described below. In this regard, production methods are not limited to the following examples.

 In the following production methods, it is sometimes effective from the point of view of the production technique to replace a certain functional group, depending on the type, with a suitable protective group, specifically with an easily convertible group in the functional group, in the stage of the raw material or of the 55 intermediate products. Subsequently, the protecting group can be removed, if necessary, to obtain the desired compound. Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and so on. Protecting groups thereof are, for example, those described in Protective Groups in Organic Synthesis, third edition (T.W. Green and P.G.M. Wuts, eds., JOHN WILLEY & SONS, INC.). These can be used appropriately depending on the reaction conditions. For the introduction and removal of 60

such protecting groups, the methods described in the reference can be suitably applied. First Production Method

 Compound (I) can be easily produced by subjecting the Carboxylic Acid Compound (III) and Aniline Derivative (II) to an amidation reaction. The amidation reaction can be carried out by general methods. For example, the method described in "Courses in Experimental Chemistry" edited by the Chemical Society of Japan, fourth edition (Maruzen), Vol. 22, pp. 137-173. Preferably, the reaction is carried out by converting the Carboxylic Acid Compound (III) into a reactive derivative such as an acid halide (acid chloride) or an acid anhydride, and subsequently reacting the resulting reactive derivative with the Aniline Derivative ( II). In the case of using a reactive carboxylic acid derivative, a base [an inorganic base 10 such as potassium carbonate, sodium hydroxide, or an organic base such as triethylamine (TEA), diisopropylethylamine, pyridine] is preferably added. In addition, the amidation reaction can be carried out by reacting the carboxylic acid in the presence of a condensing agent [1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (WSC), 1,1'-carbonylbis-1H-imidazole (CDI)]. In this case, additives such as 1-hydroxybenzotriazole (HOBt) may be added. The reaction temperature can be appropriately selected depending on the raw material compound used. The usable solvent includes those that are inert to the reaction, for example the solvents of the aromatic hydrocarbon series such as benzene, toluene; solvents of the series of ethers such as tetrahydrofuran (THF), 1,4-dioxane; solvents of the halogenated hydrocarbon series such as dichloromethane, chloroform; Amide series solvents such as N, N-dimethylformamide (DMF), N, N-dimethylacetamide, etc .; basic solvents such as pyridine. The solvent is appropriately selected depending on the type of compound 20 raw material and can be used alone or as a mixture of two or more thereof. The aforementioned raw material compounds can be easily produced using known reactions, for example those described in "Courses in Experimental Chemistry" edited by the Chemical Society of Japan, fourth edition (Maruzen), in the International Publication WO 02/38554 . The typical production methods thereof are described below. 25

image 1

Production method of Compound (III)

(In the formula, Hal means halogen, R means a group capable of forming an ester residue, such as a lower alkyl, an aralkyl).

image 1

 In the above reaction scheme, the amidation can be carried out in the same manner as in the first previous production method. The N-alkylation of Compound (VI) can be carried out using the Halogenated Alkyl Compound (VII) according to usual methods, for example the method described in the "Courses in Experimental Chemistry", fourth edition (Maruzen), Vol 20, pp. 279-318, previously mentioned. The reaction can be carried out under a temperature ranging from cooling to heating. Examples of the usable solvent include solvents inert to the reaction, for example those exemplified for amidation in the first production method. The reaction is preferably carried out in the presence of a base such as potassium carbonate, sodium hydroxide, sodium hydride. Amidation can be performed in the same manner as in the first method of previous production. Here, the amidation can be carried out first and then N-alkylation can be performed.

 Deprotection to obtain the Carboxylic Acid Compound (III) can be performed by appropriately applying a general method depending on the type of ester. In the case of alkyl esters 40 such as an ethyl ester, deprotection can preferably be carried out by treating it with a

base such as an aqueous solution of sodium hydroxide. In the case of aralkyl esters such as a benzyl ester, deprotection can be carried out by reducing it with palladium-carbon (Pd-C) under a hydrogen atmosphere. The reactions can be carried out according to the method described in "Protective Groups in Organic Synthesis", third edition, mentioned above.

 A desired raw material compound can be produced by subjecting the compound having a certain type of substituent to a substitution modification reaction well known to those skilled in the art.

 Compound (I) of the present invention obtained in this way is isolated and purified in its free form or as a salt thereof after a salt formation process by a general method. Isolation and purification are performed using general chemical procedures such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various chromatographic techniques.

Reference Examples

 The effects of the medicament of the present invention were confirmed by the following pharmacological tests.

Example 1. Helicase-primase inhibitory activity 15

 Using baculovirus to express the respective proteins of UL5, UL52 and UL8 constituting a helicase-primase complex of HSV-1 (obtained from Dr. Nigel D. Stow, Medical Research Council, UK), a helicase-primase complex of HSV was prepared -1 recombinant by the method described in a report by Crute et al. (J. B. C., 1991, Vol. 266, pp. 21252-21256). The detection of the DNA-dependent ATPase activity of the HSL-1 helicase-primase complex was carried out by reference to the method described in a report by Crute et al. (J. B. C., 1991, Vol. 266, pp. 4484-4488). Briefly, 520 ng of the HSV-1 helicase-primase complex were allowed to undergo the reaction at 30 ° C for 30 minutes in a reaction liquid containing 20 μg / ml of heat-denatured bovine sperm DNA and 2 mM ATP, and subsequently determined the concentration of phosphoric acid formed by the hydrolysis of ATP to give ADP and monophosphate by the activity of ATPase by adding the same volume of Malachite Green reagent (0.03% Malachite Green, 0.1% ammonium molybdate, 4.8% sulfuric acid) and measuring the resulting absorbance at 650 nm. The concentration of each compound to be analyzed that inhibited 50% (IC50 value) of the DNA-dependent ATPase activity of the helicase-primase complex of HSV-1 was calculated, as the concentration that halves the phosphoric acid concentration at the time when the compound is not added. The results are shown in the following Table.

[Table 1] 30

 Compounds to be tested

 IC50 value (μM)

 Compound of Preparation 2

 0.084

 Compound of Preparation 27

 0.11

Example 2. Model of HSV-1 skin infection in mice (in vivo assay)

 Using a model of HSV-I skin infection in mice prepared according to the method of H. Machida et al. (Antiviral Res., 1992, 17, 133-143), the in vivo activity of the pharmaceutical composition of the present invention was analyzed. The skin of each nude mouse HR-1 [females, 7 weeks old] was scraped lengthwise and several times using a needle and a virus suspension (HSV-1 strain WT-51, 1.5 x 104 PFU / 15 μl) was poured dropwise into the scarified region to produce an infection, while the mouse remained anesthetized with diethyl ether.

 With respect to the compounds to be tested, VCV was used as a polymerase inhibitor and prepared as a suspension in methyl cellulose; the compound of Preparation 2, 1,1- N- (4-methylphenyl) -40 N- (2 - {[4- (1,3-oxazol-4-yl) phenyl] amino} -2-oxoethyl dioxide ) tetrahydro-2H-thiopiran-4-carboxamide, which is described below, was used as a helicase-primase inhibitor and was prepared as a suspension in methyl cellulose and they were administered orally at the doses in the following table twice at day for 5 days, starting 3 hours after infection. The symptoms of skin lesions caused by HSV-1 infection were classified according to the following scores for 17 days: 45

 Score 0: no signs of infection.

 Score 1: small localized vesicles, barely noticeable.

 Score 2: slight spread of the vesicles.

 Score 3: formation of large vesicle plates.

 Score 4: Zosteriform vesicles.

 Score 5: formation of large ulcer plaques.

 Score 6: Zosteriform vesicles with severe large ulcers.

 Score 7: paralysis of the hind limbs or death. 5

 The AUC value was calculated from the mean disease score of each group, and the disease inhibitory rate of the group to which each test compound had been administered relative to the placebo group was calculated using the AUC. The results are shown in the following table. The group in which VCV had been used simultaneously with the compound of Preparation 2, showed good lesion inhibitory activity compared to the group administered only with VCV, and in the group in which 10 mg had been used simultaneously. / kg of VCV and 3 mg / kg of the compound of Preparation 2 the lesions were almost completely inhibited.

[Table 2]

 VCV dose (mg / kg) Dose of the compound of Preparation 2 (mg / kg) Injury inhibition rate (%)

 Comparative Example 1

 0 0 0

 Comparative Example 2

 0 1 38

 Comparative Example 3

 0 3 52

 Comparative Example 4

 10 0 45

 Comparative Example 5

 30 0 57

 Simultaneous use 1 of the present invention

 10 1 76

 Simultaneous use 2 of the present invention

 10 3 83

 Simultaneous use 3 of the present invention

 30 1 86

 Simultaneous use 4 of the present invention

 30 3 91

 In the same manner as described above, VCV was used as an inhibitor of polymerase and the compound of Preparation 27, 1,1- N- (2,6-dimethylphenyl) -N- (2 - {[4 - (1,2,4-oxadiazol-3-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopiran-4-carboxamide, which is described later, was used as a helicase-primase inhibitor, with the results shown in the following table.

[Table 3]

 VCV dose (mg / kg) Dose of compound of Preparation 27 (mg / kg) Inhibition rate of lesions (%)

 Comparative Example 6

 0 0 0

 Comparative Example 7

 0 1 33

 Comparative Example 8

 0 3 68

 Comparative Example 9

 10 0 42

 Comparative Example 10

 30 0 52

 Simultaneous use 5 of the present invention

 10 1 66

 Simultaneous use 6 of the present invention

 10 3 86

 Simultaneous use 7 of the present invention

 30 1 88

 Simultaneous use 8 of the present invention

 30 3 100

 The group in which 10 mg / kg of VCV and 3 mg / kg of the compound of Preparation 27 were used simultaneously, the group in which 30 mg / kg of VCV and 1 mg / kg of the compound of the Preparation were used simultaneously 27 and the group in which 30 mg / kg of VCV and 3 mg / kg of the compound of Preparation 27 were used simultaneously, showed good lesion-inhibiting activity compared to the group to which only VCV was administered, and In the group in which 30 mg / kg of VCV and 3 mg / kg of the compound of Preparation 27 were used simultaneously, the lesions were completely inhibited.

 According to the above, it was confirmed in the animal model in vivo that the anti-herpes virus activity was reinforced by the simultaneous use of a polymerase inhibitor such as VCV or similar and a helicase-primase inhibitor, and a more potent effect would be expected even at the same dose of the conventional polymerase inhibitor, or the same effect or effect greater than a dose of the polymerase inhibitor would be expected to be less than that of conventional cases. Even in the case where sufficient activity could not be obtained by a mechanism, a good anti-herpes virus activity could be achieved by the simultaneous use of both agents, based on their synergistic effect by two mechanisms, so that they can Obtain excellent clinical effects.

(Preparations) 15

 Production examples of Compound (I), which is an active ingredient of the present invention, are shown below as Preparations. Herein, many of the raw material compounds for use in the following reactions are known from the Patent Reference 1 (International Publication WO 02/38554) form and may therefore be readily available in accordance with the methods described in These known references. Examples of production of new compounds among the 20 raw materials are shown below in the Reference Examples.

Reference Example 1:

 A 5% palladium-carbon powder was added to a mixed suspension in ethanol-tetrahydrofuran of 4- (4-nitrophenyl) -1,3-oxazole and stirred for 12 hours at room temperature under a hydrogen atmosphere. The reaction solution was filtered through Celite and the filtrate was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain [4- (1,3-oxazol-4-yl) phenyl] amine (pale yellow solid). MS-Electronic Impact (M) +: 160.

Reference Example 2:

 Potassium carboxylate and ethyl bromoacetate were added to a DMF solution of 4-methylaniline and heated while stirring. Water and ethyl acetate were added to the reaction mixture. After the organic layer was separated, washed and dried, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was dissolved in methylene chloride and the resulting solution was

They added pyridine, 1,1-tetrahydro-2H-thiopyran-4-carbonyl chloride dioxide and stirred. Subsequently, the reaction solution was concentrated and 1 M hydrochloric acid and chloroform were added thereto. The separated organic layer was washed and dried and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain {[(1,1-dioxotetrahydro-2H-thiopyran-4-yl) carbonyl] (4-methylphenyl) amino} acetate (colorless oily product). FAB-MS [(M + H) +]: 354. 5

Reference Examples 3 to 15:

 The compounds of Reference Examples 3 to 15, which are described in Table 4 below, were obtained in the same manner as in Reference Example 2.

Preparation 1:

 To an ethanol solution (10 ml) of ethyl acetate {(2,6-dimethylphenyl) [(1,1-tetrahydro-2H-10 thiopyran-4-yl) carbonyl] amino} (735 mg) was added a 1 M aqueous solution of sodium hydroxide (2.3 ml). The mixture was stirred at room temperature for 5 hours. After adding 1M hydrochloric acid to the reaction mixture to make the solution acidic, water and chloroform were added thereto to separate the organic layer. Subsequently, the organic layer was dried over anhydrous sodium sulfate and filtered and then the solvent was evaporated under reduced pressure. After the resulting crude carboxylic acid product was dissolved in chloroform (15 ml), WSC · HCl (422 mg) and [4- (1,3-oxazol-4-yl) phenyl] were added sequentially to the resulting solution. amine (320 mg), which was stirred at room temperature for 4 hours. After adding a saturated aqueous solution of sodium hydrogen carbonate and chloroform to the reaction solution, the organic layer was separated. The organic layer was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered, from which the solvent was evaporated under reduced pressure. The resulting crude product 20 was washed in hexane-ethyl acetate (= 3/2) and subsequently recrystallized from ethanol to obtain 1,1- N- (2,6-dimethylphenyl) -N- (2- { [4- (1,3-Oxazol-4-yl) phenyl] amino} -2-oxoethyl) tetrahydro-2H-thiopyran-4-carboxamide (colorless crystal) with a yield of 610 mg.

Preparations 2 - 40:

 The compounds of Preparations 2 to 40 shown in Tables 5 to 12 below were obtained in the same manner as in Preparation 1.

 The physicochemical properties of the compounds of the Reference Examples are shown in Table 4, while Tables 5 to 12 show the structures and physicochemical properties of the Compounds of the Preparations.

 Abbreviations in the tables indicate the following. Ref: Reference Example; Ex: 30 Preparation; Dat: physicochemical properties {F +: FAB-MS [(M + H) +]; F-: FAB-MS [(M-H]) -]; N1: 1H-NMR (DMSO-d6, internal TMS standard); mp: melting point (° C), the solvent for crystallization is shown in brackets}; Ph: phenyl; Me: methyl; Et: ethyl; and iPr: isopropyl. Here, the numerical figure before each substituent indicates the position of its substitution. For example, 3,4- (Cl) 2-5-F-Ph indicates a 3,4-dichloro-5-fluorophenyl group.

[Table 4]

 Ref

 A R Dat Ref A R Dat

 3

 2,3- (Me) 2-Ph Et F +: 368 4 4-Me-Ph Et F +: 354

 5

 2,5- (Me) 2-Ph Et F +: 368 6 3-Me-Ph Et F +: 354

 7

 3,4- (Me) 2-Ph Et F +: 368 8 2-Me-Ph Et F +: 354

 9

 2,4,6- (Me) 3-Ph Et F +: 382 10 2,4- (Me) 2-Ph Et F +: 368

 eleven

 4-F-3-Me-Ph Et F +: 372 12 2.6- (Me) 2-Ph Et F +: 368

 13

 3-Br-4-Me-Ph Et F +: 432,434 14 4-F-2,6- (Me) 2-Ph Et F +: 386

 fifteen

 3,5- (Me) 2-Ph Et F +: 368

image 1

[Table 5]

 Former

 To dat

 one

 2.6- (Me) 2-Ph F +: 482 N1: 1.87-2.42 (5H, m), 2.13 (6HX0.1, s), 2.33 (6HX0.9, s), 2.97-3.27 (4H, m), 4.19 (2HX0.9, s), 4.48 (2HX0.1, s), 7.07-7.25 (3H, m), 7, 62-7.66 (2H, m), 7.72-7.75 (2H, m), 8.43 (1H, d), 8.54 (1H, d), 10.15 (1H, wide s ) mp: 224-227 (EtOH)

 2

 4-Me-Ph F +: 468 N1: 1.98-2.06 (4H, m), 2.34 (3H, s), 2.68-2.70 (1H, m), 2.97-3 , 02 (4H, m), 4.35 (2H, s), 7.28 (2H, d), 7.36 (2H, d), 7.63-7.66 (2H, m), 7, 72-7.76 (2H, m), 8.43 (1H, s), 8.54 (1H, s), 10.14 (1H, s) mp: 199-201 (EtOH-H2O)

 3

 3-Me-Ph F +: 468 N1: 2.01-2.09 (4H, m), 2.35 (3H, s), 2.71 (1H, m), 2.93-3.06 (4H , m), 4.36 (2H, s), 7.17-7.38 (4H, m), 7.64 (2H, d), 7.73 (2H, d), 8.43 (1H, d), 8.54 (1H, d), 10.15 (1H, s)

image 1

 4

 2-Me-Ph F +: 468 N1: 1.88-2.15 (4H, m), 2.15 (3HX0.1, s), 2.26 (3HX0.9, s), 2.41-2 , 46 (1H, m), 2.83-3.05 (4H, m), 3.86 (1HX0.9, d) 4.20 (1HX0.1, d), 4.74 (1HX0.9, d), 4.84 (1HX0.1, d), 7.09-7.77 (8H, m), 8.43 (1H, d), 8.53 (1H, d), 10.14 (1HX0 , 9, s), 10.19 (1HX0.1, s) mp: 220-221 (EtOH)

[Table 6]

 5

 2,3- (Me) 2-Ph F +: 482 N1: 1,85-2,12 (4H, m), 2,03 (3HX0,1, s), 2,15 (3HX0,9, s), 2.25 (3HX0.1, s), 2.31 (3HX0.9, s), 2.42-2.47 (1H, m), 2.83-2.90 (1H, m), 3, 00-3.22 (3H, m), 3.84 (1HX0.9, d), 4.16 (1HX0.1, d), 4.72 (1HX0.9, d), 4.84 (1HX0, 1, d), 7.07-7.36 (3H, m), 7.62-7.66 (2H, m), 7.71-7.76 (2H, m), 8.43 (1H, s wide), 8.54 (1H, d), 10.15 (1HX0.9, s), 10.16 (1HX0.1, s) mp: 185-187 (EtOH)

 6

 2,4- (Me) 2-Ph F +: 482 N1: 1.88-2.50 (5H, m), 2.09 (3HX0.1, s), 2.21 (3HX0.9, s), 2.25 (3HX0.1, s), 2.30 (3HX0.9, s), 2.85-3.20 (4H, m), 3.81 (1HX0.9, d), 4.17 ( 1HX0.1, d), 4.72 (1HX0.9, d), 4.81 (1HX0.1, d), 6.97-7.39 (3H, m), 7.62-7.66 ( 2H, m), 7.72-7.76 (2H, m), 8.43 (1H, s), 8.54 (1H, s), 10.11 (1HX0.9, s), 10.17 (1HX0.1, s) mp: 176-177 (EtOH)

 7

 2.5- (Me) 2-Ph F +: 482 N1: 1.86-2.51 (5H, m), 2.08 (3HX0.1, s), 2.20 (3HX0.9, s), 2.22 (3HX0.1, s), 2.30 (3HX0.9, s), 2.87-3.26 (4H, m), 3.84 (1HX0.9, d), 4.21 ( 1HX0.1, d), 4.70 (1HX0.9, d), 4.80 (1HX0.1, d), 6.92-7.32 (3H, m), 7.63-7.65 ( 2H, m), 7.72-7.76 (2H, m), 8.43 (1H, s), 8.54 (1H, s), 10.12 (1HX0.9, s), 10.17 (1HX0.1, s) mp: 201-202 (EtOH)

 8

 3.4- (Me) 2-Ph F +: 482 N1: 1.92-2.08 (4H, m), 2.09 (3H, s), 2.24 (3H, s), 2.71 ( 1H, s), 2.94-3.06 (4H, m), 4.33 (2H, s), 7.17-7.24 (3H, m), 7.64 (2H, d), 7 , 73 (2H, d), 8.43 (1H, s), 8.54 (1H, s), 10.12 (1H, s)

 9

 3.5- (Me) 2-Ph F +: 482 N1: 1.96-2.14 (4H, m), 2.30 (6H, s), 2.73 (1H, m), 2.95- 3.04 (4H, m), 4.33 (2H, s), 7.02 (1H, s), 7.08 (2H, s), 7.64 (2H, d), 7.73 (2H , d), 8.43 (1H, s), 8.54 (1H, s), 10.12 (1H, s) mp: 205-206 (EtOH)

[Table 7]

 10

 2,4,6- (Me) 3-Ph F +: 496 N1: 1,87-2,45 (5H, m), 2,08 (3HX0,1, s), 2,09 (6HX0,1, s ), 2.27 (3HX0.9, s), 2.28 (6HX0.9, s), 3.01-3.26 (4H, m), 4.16 (2HX0.9, s), 4, 44 (2HX0.1, s), 6.88 (2HX0.1, s), 7.01 (2HX0.9, s), 7.61-7.65 (2H, m), 7.71-7, 75 (2H, m), 8.43 (1H, s), 8.54 (1H, s), 10.12 (1HX0.9, s), 10.14 (1HX0.1, s) mp: 237- 238 (EtOH)

 eleven

    F +: 494 N1: 2.01-2.08 (6H, m), 2.70-3.06 (9H, m), 4.34 (2H, s), 7.13-7.32 (3H, m), 7.64 (2H, d), 7.73 (2H, d), 8.43 (1H, s), 8.54 (1H, s), 10.13 (1H, s)

 12

 3-Cl-4-Me-Ph F +: 502 N1: 2.01-2.06 (4H, m), 2.36 (3H, s), 2.68-2.75 (1H, m), 3 , 01-3.06 (4H, m), 4.37 (2H, s), 7.37-7.40 (1H, m), 7.46 (1H, d), 7.60-7.66 (3H, m), 7.74 (2H, d), 8.44 (1H, s), 8.55 (1H, s), 10.18 (1H, s) mp: 146-148 (EtOH)

 13

 4-Cl-3-Me-Ph F +: 502 N1: 2.00-2.06 (4H, m), 2.36 (3H, s), 2.68-2.75 (1H, m), 3 , 01-3.04 (4H, m), 4.36 (2H, s), 7.33-7.36 (1H, m), 7.48-7.52 (2H, m), 7.64 (2H, d), 7.73 (2H, d), 8.43 (1H, s), 8.54 (1H, s), 10.18 (1H, s) mp: 133-135 (EtOH)

 14

 3-F-4-Me-Ph F +: 486 N1: 2.00-2.05 (4H, m), 2.26 (3H, s), 2.70-2.77 (1H, m), 3 , 01-3.03 (4H, m), 4.36 (2H, s), 7.24-7.26 (1H, m), 7.32-7.41 (2H, m), 7.64 (2H, d), 7.73 (2H, d), 8.43 (1H, s), 8.54 (1H, s), 10.17 (1H, s) mp: 135-137 (EtOH)

 fifteen

 3-Br-4-Me-Ph F +: 546, 548 N1: 2.00-2.06 (4H, m), 2.38 (3H, s), 2.68-2.74 (1H, m) , 3.01-3.04 (4H, m), 4.36 (2H, s), 7.41-7.47 (2H, m), 7.64 (2H, d), 7.73-7 , 76 (3H, d), 8.43 (1H, s), 8.54 (1H, s), 10.18 (1H, s) mp: 154-155 (EtOH)

image 1

[Table 8]

 16

 5-F-2-Me-Ph F +: 486 N1: 1.88-2.15 (4H, m), 2.11 (3HX0.1, s), 2.23 (3HX0.9, s), 2 , 45-2.49 (1H, m), 2.96-3.16 (4H, m), 3.92 (1HX0.9, d), 4.27 (1HX0.1, d), 4.70 (1HX0.9, d), 4.82 (1HX0.1, d), 6.95-6.98 (1HX0.1, m), 7.06-7.10 (1HX0.1, m), 7 , 20-7.25 (1HX0.9, m), 7.29-7.33 (1HX0.1, m), 7.37-7.40 (1HX0.9, m), 7.42-7, 46 (1HX0.9, m), 7.65 (2H, d), 7.74 (2H, d), 8.43 (1H, s), 8.54 (1H, s), 10.18 (1HX0 , 9, s), 10.23 (1HX0.1, s) mp: 235-236 (EtOH)

 17

 3-F-2,4- (Me) 2-Ph F +: 500 N1: 1,88-2,23 (4H, m), 2,03 (3HX0,1, s), 2,16 (3HX0,9 , s), 2.20 (3HX0.1, s), 2.26 (3HX0.9, s), 2.47-2.54 (1H, m), 2.87-3.17 (4H, m ), 3.91 (1HX0.9, d), 4.25 (1HX0.1, d), 4.66 (1HX0.9, d), 4.80 (1HX0.1, d), 6.88 ( 1HX0.1, d), 7.10 (1HX0.1, dd), 7.21 (1HX0.9, dd), 7.28 (1HX0.9, d), 7.64 (2H, d), 7 , 73 (2H, s), 8.43 (1H, s), 8.54 (1H, s), 10.14 (1HX0.9, s), 10.20 (1HX0.1, s) mp: 185 -186 (EtOH)

 18

 4-F-3.5- (Me) 2-Ph F +: 500 N1: 2.00-2.05 (4H, m), 2.24 (6H, s), 2.67-2.74 (1H , m), 3.00-3.04 (4H, m), 4.33 (2H, s), 7.23 (2H, d), 7.65 (2H, d), 7.74 (2H, d), 8.43 (1H, s), 8.54 (1H, s), 10.15 (1H, s) mp: 188-189 (EtOH)

 19

 3,5-F2-4-Me-Ph F +: 504 N1: 1.99-2.05 (4H, m), 2.17 (3H, s), 2.75-2.82 (1H, m) , 2.99-3.10 (4H, m), 4.37 (2H, s), 7.28 (2H, d), 7.65 (2H, d), 7.74 (2H, d), 8.44 (1H, s), 8.55 (1H, s), 10.21 (1H, s) mp: 221-223 (EtOH)

 twenty

 2-F-4-Me-Ph F +: 486 N1: 1.89-2.11 (4H, m), 2.30 (3HX0.1, s), 2.36 (3HX0.9, s), 2 , 60-2.68 (1H, m), 3.01-3.26 (4H, m), 3.94 (1HX0.9, d), 4.02 (1HX0.1, d), 4.50 (1HX0.1, d), 4.76 (1HX0.9, d), 7.00 (1HX0.1, d), 7.09 (1HX0.1, d), 7.12 (1HX0.9, d ), 7.24 (1HX0.9, d), 7.38 (1HX0.1, dd), 7.50 (1HX0.9, dd), 7.63 (2H, d), 7.73 (2H, d), 8.44 (1H, s), 8.55 (1H, s), 10.17 (1HX0.9, s), 10.23 (1HX0.1, s)

[Table 9]

 Former

 To dat

 twenty-one

 4-Me-Ph F +: 469 N1: 1.94-2.11 (4H, m), 2.34 (3H, s), 2.65-2.75 (1H, m), 2.92-3 , 08 (4H, m), 4.38 (2H, s), 7.28 (2H, d), 7.37 (2H, d), 7.79 (2H, d), 8.00 (2H, d), 9.66 (1H, s), 10.38 (1H, s) mp: 203-205 (EtOH)

 22

 3-Me-Ph F-: 467 N1: 1.96-2.11 (4H, m), 2.35 (3H, s), 2.65-2.76 (1H, m), 2.92- 3.09 (4H, m), 4.39 (2H, s), 7.20-7.39 (4H, m), 7.79 (2H, d), 8.00 (2H, d), 9 , 66 (1H, s), 10.38 (1H, s)

 2. 3

 2-Me-Ph F +: 469 N1: 1.88-2.26 (4H + 3H, m), 2.42-2.52 (1H, m), 2.84-3.18 (4H, m) , 3.91 (1HX0.9, d), 4.44 (1HX0.1, d), 4.75 (1HX0.9, d), 4.87 (1HX0.1, d), 7.08-7 , 54 (4H, m), 7.75-7.81 (2H, m), 7.97-8.04 (2H, m), 9.66 (1HX0.9, s), 9.67 (1HX0 , 1, s), 10.37 (1HX0.9, s), 10.41 (1HX0.1, s) mp: 216-217 (MeOH)

 24

 2,3- (Me) 2-Ph F-: 481 N1: 1,83-2,31 (4H + 3H + 3H, m), 2,42-2,54 (1H, m), 2,82- 3.16 (4H, m), 3.88 (1HX0.9, d), 4.19 (1HX0.1, d), 4.72 (1HX0.9, d), 4.87 (1HX0.1, d), 7.05-7.37 (3H, m), 7.75-7.80 (2H, m), 7.97-8.03 (2H, m), 9.66 (1HX0.9, s), 9.66 (1HX0.1, s), 10.35 (1HX0.9, s), 10.38 (1HX0.1, s) mp: 223-225 (EtOH)

 25

 2.3- (Me) 2-Ph F-: 481 N1: 1.84-2.33 (4H + 3H + 3H, m), 2.42-2.52 (1H, m), 2.84- 3.19 (4H, m), 3.86 (1HX0.9, d), 4.21 (1HX0.1, d), 4.73 (1HX0.9, d), 4.84 (1HX0.1, d), 6.95-7.40 (3H, m), 7.75-7.81 (2H, m), 7.98-8.02 (2H, m), 9.66 (1HX0.9, s), 9.66 (1HX0.1, s), 10.35 (1HX0.9, s), 10.39 (1HX0.1, s) mp: 139-141 (EtOH)

image 1

[Table 10]

 26

 2.5- (Me) 2-Ph F-: 481 N1: 1.84-2.32 (4H + 3H + 3H, m), 2.42-2.52 (1H, m), 2.87- 3.18 (4H, m), 3.89 (1HX0.9, d), 4.25 (1HX0.1, d), 4.72 (1HX0.9, d), 4.83 (1HX0.1, d), 6.92-7.34 (3H, m), 7.76-7.82 (2H, m), 7.98-8.04 (2H, m), 9.66 (1HX0.9, s), 9.67 (1HX0.1, s), 10.37 (1HX0.9, s), 10.39 (1HX0.1, s) mp: 214-217 (EtOH)

 27

 2.6- (Me) 2-Ph F-: 481 N1: 1.88-2.42 (5H + 6H, m), 2.98-3.27 (4H, m), 4.22 (2HX0, 86, s), 4.51 (2HX0.14, s), 7.1-7.3 (3H, m), 7.76-7.81 (2H, m), 7.99-8.03 ( 2H, m), 9.66 (1H, s), 10.38 (1H, s) mp: 220-222 (EtOH-H2O)

 28

 3.4- (Me) 2-Ph F +: 483 N1: 1.97-2.20 (4H, m), 2.24 (6H, s), 2.67-2.76 (1H, m), 2.96-3.30 (4H, m), 4.37 (2H, s), 7.17-7.27 (3H, m), 7.79 (2H, d), 8.00 (2H, d), 9.66 (1H, s), 10.36 (1H, s) mp: 141-143 (EtOH)

 29

 3.5- (Me) 2-Ph F +: 483 N1: 1.98-2.12 (4H, m), 2.30 (6H, s), 2.65-2.78 (1H, m), 2.93-3.10 (4H, m), 4.36 (2H, s), 7.00-7.12 (3H, m), 7.79 (2H, d), 8.00 (2H, d), 9.66 (1H, s), 10.37 (1H, s) mp: 197-198 (iPrOH)

 30

       F-: 495 N1: 1.83-2.52 (4H + 9H + 1H, m), 2.99-3.26 (4H, m), 4.18 (2HX0.9, s), 4.48 (2HX0.1, s), 6.88 (2HX0.1, s), 7.01 (2HX0.9, s), 7.74-7.82 (2H, m), 7.94-8.03 (2H, m), 9.66 (1H, s), 10.36 (1H, s) mp: 180-190 (EtOH)

 31

       F-: 499 N1: 1.82-2.44 (6H + 5H, m), 2.98-3.30 (4H, m), 4.21 (2HX0.85, s), 4.50 (2HX0 , 15, s), 6.95 (2HX0.15, d), 7.08 (2HX0.85, d), 7.75-7.82 (2H, m), 7.97-8.04 (2H , m), 9.66 (1HX0.85, s), 9.66 (1HX0.15, s), 10.40 (1H, wide s) mp: 226-229 (EtOH-MeCN-H2O)

image 1

image 1

[Table 11]

 32

       F +: 487 N1: 1.97-2.11 (4H, m), 2.26 (3H, wide s), 2.63-2.74 (1H, m), 2.95-3.07 (4H , m), 4.38 (2H, s), 7.21-7.45 (3H, m), 7.79 (2H, d), 8.00 (2H, d), 9.66 (1H, s), 10.39 (1H, s) mp: 136-138 (EtOH)

 33

       F-: 493 N1: 1.96-2.20 (6H, m), 2.70-2.78 (1H, m), 2.84-3.08 (8H, m), 4.37 (2H , s), 7.04-7.33 (3H, m), 7.79 (2H, d), 8.00 (2H, d), 9.66 (1H, s), 10.37 (1H, s)

 3. 4

 4-Me-3-Br-Ph F-: 546 N1: 1.96-2.16 (4H, m), 2.38 (3H, s), 2.66-2.77 (1H, m), 2.96-3.08 (4H, m), 4.39 (2H, s), 7.40-7.49 (2H, m), 7.73-7.82 (3H, m), 8, 00 (2H, d), 9.66 (1H, s), 10.41 (1H, s) mp: 203-206 (iPrOH)

 35

 3-F-4-Me-Ph F +: 487 N1: 1.97-2.07 (4H, m), 2.26 (3H, s), 2.69-2.77 (1H, m), 2 , 99-3.03 (4H, m), 4.39 (2H, s), 7.22-7.28 (1H, m), 7.31-7.42 (2H, m), 7.80 (2H, d), 7.99 (2H, d), 9.66 (1H, s), 10.40 (1H, s) mp: 200-203 (EtOH)

 36

 3-Cl-4-Me-Ph F +: 503 N1: 1.97-2.11 (4H, m), 2.36 (3H, s), 2.65-2.78 (1H, m), 2 , 95-3.08 (4H, m), 4.39 (2H, s), 7.39 (1H, dd), 7.45 (1H, d), 7.60 (1H, d), 7, 80 (2H, d), 7.99 (2H, d), 9.65 (1H, s), 10.40 (1H, s) mp: 204-205 (EtOH)

 37

 4-Cl-3-Me-Ph F +: 503 N1: 1.95-2.09 (4H, m), 2.36 (3H, s), 2.65-2.76 (1H, m), 2 , 95-3.07 (4H, m), 4.39 (2H, s), 7.36 (1H, dd), 7.48 (1H, d), 7.51 (1H, d), 7, 80 (2H, d), 7.99 (2H, d), 9.66 (1H, s), 10.40 (1H, s) mp: 196-199 (EtOH)

 38

 4-F-3.5- (Me) 2-Ph F +: 501 N1: 1.94-2.12 (4H, m), 2.24 (6H, s), 2.64-2.74 (1H , m), 2.94-3.08 (4H, m), 4.35 (2H, s), 7.23 (2H, d), 7.79 (2H, d), 7.99 (2H, d), 9.66 (1H, s), 10.38 (1H, s)

image 1

image 1

[Table 12]

 39

 3-F-2,4- (Me) 2-Ph F +: 501 N1: 1,84-2,34 (4H + 3H + 3H, m), 2,48-2,55 (1H, m), 2 , 85-3.22 (4H, m), 3.98 (1HX0.9, d), 4.30 (1HX0.1, d), 4.65 (1HX0.9, d), 4.81 (1HX0 , 1, d), 7.22 (1H, t), 7.27 (1H, d), 7.78 (2H, d), 7.98 (2H, d), 9.66 (1H, s) , 10.37 (1HX0.9, s), 10.51 (1HX0.1, s)

 40

 2-F-4-Me-Ph F +: 487 N1: 1.90-2.18 (4H, m), 2.30 (3HX0.1, s), 2.36 (3HX0.9, s), 2 , 62-2.68 (1H, m), 3.01-3.23 (4H, m), 3.99 (1H, d), 4.77 (1H, d), 7.13 (1H, d ), 7.25 (1H, d), 7.50 (1H, dd), 7.77 (2H, d), 7.99 (2H, d), 9.66 (1H, s), 10.40 (1HX0.9, s), 10.45 (1HX0.1, s) mp: 197-198 (EtOH)

Industrial Applicability

 By separate administration of an acyclovir, valacyclovir or famciclovir polymerase inhibitor as a conventional anti-herpes virus agent, with a helicase-primase inhibitor of general formula (I) having a different functional mechanism, the herpes anti-virus agent The present invention achieved the anti-herpes virus activity. Therefore, it is particularly effective in cases where a sufficient therapeutic effect cannot be achieved only with a polymerase inhibitor. In addition, since the doses of both agents can be kept low due to their separate use, it is possible to obtain a treatment effect that is similar or greater than in the case of the respective individual administrations, together with a decrease in undesirable actions concerning both Agents Accordingly, the herpes anti-virus agent of the present invention is useful as an anti-herpes virus agent which in particular has high safety for the prevention or treatment of different herpes virus infections such as chickenpox ("chickenpox" ) associated with VZV infection, shingles associated with recurrent latent VZV infection, cold sores and herpetic encephalitis associated with HSV-1 infection, genital herpes associated with HSV-2 infection. fifteen

Claims (3)

 1.- An anti-herpes virus agent characterized by the combination of a compound of general formula (I): image 1 in which Z is a 1,2,4-oxadiazol-3-yl or 4-oxazolyl group; A is a phenyl group that is substituted with at least one methyl group and which may also have 1 or 2 substituents selected from the group consisting of a methyl group or halogen atoms, or a 5-indanyl group; with a polymerase inhibitor selected from acyclovir, 5 valacyclovir and famciclovir; wherein the compound of general formula (I) and the polymerase inhibitor must be administered separately.  2. An antiviral agent according to claim 1, wherein the polymerase inhibitor is valacyclovir.